This application addresses broad NIH Challenge Area 04: Clinical Research and specific Challenge Topic 04-DA-101: Evaluation of novel, rationalized poly-pharmacotherapeutic treatment strategies for substance abuse. The problem of cocaine dependence remains a major medical, social, and legal concern, and there is a pressing need for a broadly effective treatment approach. Dozens of medications have been evaluated in clinical trials, and despite these efforts not one has proved effective as a treatment. The most promising medication evaluated to date is modafinil, which has been shown to reduce the euphoric effects produced by intravenous cocaine, to reduce smoked cocaine self-administration and associated positive subjective effects, and to reduce cocaine use in a double-blind, placebo-controlled clinical trial. Subsequently, however, findings from a large, multi-site, outpatient clinical trial indicated that modafinil treatment was no better than placebo for improving abstinence from cocaine or for reducing cocaine-positive urines. Recent data indicates that during chronic treatment modafinil produces substantial dopamine transporter (DAT) inhibition. Given that cocaine inhibits DA, norepenepherine (NE) and serotonin (5-HT) reuptake, it is highly likely that targeting more than one neurotransmitter system will be necessary for a medication to be effective. Assuming that this statement is true, we hypothesize that a combination pharmacotherapeutic approach that concurrently modulates multiple neurotransmitter systems will likely demonstrate a clinically significant level of efficacy above trials in which a single medication is used. The proposed approach is based on preclinical data indicating that medications that increase brain 5-HT levels reduce the effects of stimulants. We hypothesize that combining modafinil with a selective serotonin reuptake inhibitor (SSRI), which will increase synaptic levels of 5-HT, will further improve the efficacy of modafinil for reducing the effects produced by cocaine. We propose the following Specific Aim: To determine the effects of treatment with modafinil (0 or 200 mg) plus the SSRI escitalopram (0 or 20 mg) on the subjective and reinforcing effects produced by smoked cocaine (0 and 25 mg) in the laboratory. We will use a placebo-controlled, double-blind, parallel-groups study design. All participants will meet DSM criteria for current cocaine dependence and will not be seeking treatment. Subjective effects will be measured using visual-analogue scales and reinforcing effects will be measured using choice procedures. This proposal represents an important research effort with considerable public health significance since it will establish a program for evaluating rational combinations of drugs that target complementary neurobiological mechanisms that underlie the effects produced by cocaine (i.e., DA and 5-HT) in cocaine-dependent individuals. PUBLIC HEALTH RELEVANCE: In this application, we will evaluate the effects of modafinil combined with escitalopram on the subjective and reinforcing effects produced by smoked cocaine in the laboratory.